Primary focal segmental glomerulosclerosis in a patient with ankylosing spondylitis: A rare presentation requiring a broad differential in nephrotic syndrome

Key Clinical Message Ankylosing spondylitis (AS) presents with renal failure and proteinuria in a minority of cases, usually due to secondary amyloidosis or IgA nephropathy. While focal segmental glomerulosclerosis (FSGS) is less common, it should still be in the differential regardless of the patient's clinical profile.

lower extremities, the physical exam was unremarkable.Cardiopulmonary examination was non-revealing as confirmed on radiography, electrocardiogram only showed sinus tachycardia.Computed tomography (CT) of the head was negative for acute intracranial pathology.Creatinine was 1.47 mg/dL as shown on Figure 1, with her baseline at 0.7 mg/dL, suggesting acute kidney injury (AKI).

| METHODS
She received several doses of intravenous hydralazine, and after lack of improvement was started on a diltiazem infusion, which was chosen due to persistent tachycardia.Renal ultrasound revealed symmetric normal sized kidneys with preserved cortical thickness and no hydronephrosis.Serum albumin was 1.8 g/dL and remained below 2 g/dL throughout the 6 days of admission.Urinalysis revealed hazy clarity, with specific gravity of 1.028, proteinuria, and glucosuria above our laboratory's upper limit as greater than 500 mg/dL, with small blood noted with a red blood cell count of 5 per high-power field.A protein:creatinine ratio was ordered, which revealed a ratio outside of our laboratory's range of measurements, with urine protein reported as above 600 mg/dL and urine creatinine at 114.0 mg/dL, suggesting a ratio of at least above 6 g.An extensive secondary hypertension workup as well as autoimmune investigation consisting of ANA, anti-scleroderma antibody, paraproteinemia workup, C3, and C4 was non-revealing.A 24-hour urine protein study resulted in 11.30 g in 24 h.The patient's blood pressure lowered throughout admission and her tachycardia resolved.She was transitioned from the diltiazem infusion to labetalol 400 mg three times daily, amlodipine 10 mg daily, and hydrochlorothiazide at 50 mg daily.Due to lack of improvement in serum creatinine levels, she underwent a kidney biopsy which returned significant for complete podocyte process effacement on electron microscopy, normal glomerular basement membrane thickness, and no electron dense deposits consistent with primary FSGS (Figure 2).Histology was also remarkable for findings consistent with FSGS (Figure 3).

| CONCLUSION AND RESULTS
The patient was discharged from our facility with the same antihypertensive regimen she was transitioned to during admission.She was scheduled for a referral to see a nephrologist outpatient for her diagnosis of FSGS and to initiate steroid treatment.

| DISCUSSION
This case presented many intriguing findings.Her clinical profile falls into the minority of cases of AS presenting with renal disease.In addition, this specific population usually presents with nephrotic syndrome that is due to secondary amyloidosis and IgA nephropathy.This patient's renal biopsy returned diagnostic of FSGS.Despite her history of obesity and OSA leading one to suspect a diagnosis of adaptive FSGS, the electron microscopy demonstrated primary FSGS.
Our patient's clinical triad of hypoalbuminemia, edema, and persistent proteinuria of greater than 3.5 g/24 h were diagnostic of nephrotic syndrome. 4ersistent proteinuria can be the result of glomerular dysfunction, tubulointerstitial disease, secretory proteinuria, or overflow proteinuria. 5Normal autoimmune and complement studies made a glomerular cause less likely.The level of bands in the serum protein electrophoresis also did not explain a predominant overflow etiology to the level of protein excretion observed, which would have been more common in amyloidosis. 5The patient's serum creatinine peaked on the second day of hospitalization and steadily decreased, which coincided with improvement in blood pressure control with diltiazem.This is due to renal autoregulation as the patient's afferent arterioles became less constricted as the blood pressure improved. 6However, the lack of improvement to the patient's baseline creatinine in the setting of nephrotic range proteinuria warranted biopsy.
Kidney disease in AS is rare but is associated with increased mortality in this population. 2Most common etiologies are amyloidosis, followed by IgA nephropathy. 2utoimmunity can cause a systemic disturbance of immunity with the central feature being loss of tolerance to normal cellular and/or extracellular proteins, pertaining to many sites including the glomerulus. 7FSGS has rarely been reported in this population.
FSGS is often postulated to be multifactorial in etiology, but the common consequence is podocyte injury. 3As podocytes have an inability to replicate, loss of podocytes leads to hypertrophy of remaining podocytes to cover more of the glomerular capillary surface. 3FSGS has several subtypes including primary and secondary. 8Secondary causes consist of adaptive, genetic, virus, and medicationassociated. 3 Adaptive FSGS is associated with hyperfiltration states, such as obesity, OSA, or high-protein diet. 3Our patient had a BMI of 43.2 and a history of OSA, which raised suspicion for adaptive FSGS.However, renal biopsy reveals only partial podocyte effacement, whereas our patient had complete effacement consistent with primary FSGS.Our patient did not receive genetic testing, and it is plausible that she had genetic variants that played a role in her podocyte injury.
Various medications have been associated with FSGS including bisphosphonates, lithium, sirolimus, and anthracycline medications including doxorubicin and daunomycin. 3Our patient's medications consisted of hydrochlorothiazide and sulfasalazine.There are no known cases, to our knowledge, of FSGS related to hydrochlorothiazide or adalimumab.There have been case reports of FSGS related to sulfasalazine, but this was not continued during admission and her creatinine continued to rise and her proteinuria persisted, making this medication less likely to be the culprit. 9rimary FSGS, formerly termed idiopathic FSGS, has been associated with circulating cytokines causing podocyte foot process effacement. 10,11Primary FSGS is defined by ruling out the likelihood of other forms of FSGS and is presumed to be caused by a yet unidentified podocytetoxic factor and is often amenable to treatment. 11The complete effacement of the foot processes of the podocytes on microscopy, as demonstrated on Figure 2, as well as proteinuria greater than 3.5 g/day and albumin consistently below 3 g/dL confirmed the diagnosis of primary FSGS in our patient.Unlike secondary subtypes, primary FSGS is expected to respond to glucocorticoid or immunosuppressive therapy.Treatment consists of high-dose glucocorticoid therapy with prednisone at a single dose of 1 mg/kg for a maximum of 80 mg for at least 4 weeks and then until complete remission is achieved or 16 weeks, followed by a taper. 8,11Remission is determined by reduction in proteinuria, with complete remission defined as a reduction of proteinuria to less than 0.3 g/day, or less than 300 mg/g urine creatinine and normal serum creatinine and serum albumin. 8,11Second-line agents in the setting of persistent proteinuria include cyclosporine or mycophenolate. 11Renin-angiotensin-aldosterone system (RAAS) blockade is recommended as well. 8rimary FSGS is a leading cause of kidney disease across patients of all clinical profiles.As research into FSGS continues to grow, providers should have a lower threshold to investigate for this cause of proteinuria, even when history suggests another cause.Providers placing primary FSGS higher in the differential diagnoses will help improve outcomes, considering that if diagnosis is confirmed via biopsy, it can be successfully treated with steroids.

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I G U R E 1 Patient's serum creatinine trend throughout hospitalization.Note the peak of serum creatinine on the second day of hospitalization, this coincided with improvement of blood pressure on the diltiazem infusion.

F I G U R E 2
Electron microscopy of patient's glomerular filtration barrier.Emphasized is a section with complete podocyte foot effacement (blue arrows), with normal glomerular basement membrane thickness, and no electron dense deposits.F I G U R E 3Periodic acid-Schiff (PAS) stain of a glomerulus from renal biopsy.Emphasized is the section of segmental sclerosis (blue arrows).